Aminoindazole derivatives as medicaments and pharmaceutical compositions including them

ABSTRACT

The present invention relates to the use of novel derivatives of general formula (I) 
                         
in which
 
R3 is a (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, aryl or heteroaryl fused to a (1-10C) cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl, alkenyl, alkynyl, CONR1R2, COOR1, SO 2 R1, C(═NH)R1 or C(═NH)NR1 radical;
 
R5, R6 and R7 are, independently of one another, chosen from the following radicals: halogen, CN, NO 2 , NH 2 , OH, OR8, COOH, C(O)OR8, —O—C(O)R8, NR8R9, NHC(O)R8, C(O)NR8R9, NHC(S)R8, C(S)NR8R9, SR8, S(O)R8, SO 2 R8, NHSO 2 R8, SO 2 NR8R9, —O—SO 2 R8, —SO 2 —O—R8, trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (1-6C)alkoxy, aryl, aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, heterocycle, cycloalkyl, alkenyl, alkynyl, adamantyl or polycycloalkyl, to treat a disease selected from the group consisting of: neurodegenerative diseases, strokes, cranial and spinal traumas and peripheral neuropathies, obesity, metabolic diseases, type II diabetes, essential hypertension, atherosclerotic cardiovascular diseases, polycystic ovaries syndrome, syndrome X, immunodeficiency and cancer.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of copending U.S. application Ser. No.11/200,713, filed on Aug. 10, 2005, which is in turn a divisional ofU.S. application Ser. No. 10/654,698, filed on Sep. 4, 2003, now U.S.Pat. No. 7,019,011 Issued Mar. 28, 2006 which is a non provisional of60/444,630, filed Feb. 4, 2003, which application claims priority fromFrench Application No. FR0215720, filed Dec. 12, 2002.

BACKGROUND OF THE INVENTION

The present invention relates to the use of derivatives of formula (I):

or their pharmaceutically acceptable salts as kinase inhibitor.

The subject matter of the invention is the use of the aminoindazolederivatives of formula (I) and their pharmaceutically acceptable saltsin the preparation of pharmaceutical compositions intended to preventand treat diseases which can result from an abnormal activity ofkinases, such as, for example, those involved in neurodegenerativediseases, Alzheimer's disease, Parkinson's disease, frontoparietaldementia, corticobasal degeneration, Pick's disease, strokes, cranialand spinal traumas and peripheral neuropathies, obesity, metabolicdiseases, type II diabetes, essential hypertension, atheroscleroticcardiovascular diseases, polycystic ovaries syndrome, syndrome X,immunodeficiency and cancer, the pharmaceutical compositions comprisingthe novel aminoindazole derivatives and their pharmaceuticallyacceptable salts and the novel aminoindazole derivatives and theirpharmaceutically acceptable salts.

Patent application WO 02/074388 describes aminoindazole derivatives oftype (a) that are potassium-channel activators

in which G is

-   Z is NX0, S or O-   E is N or CX1-   Y is halogen, X2 or OX2-   X0, X1 and X2 are halogen, alkyl or a substituted alkyl-   A, B and D are hydrogen, halogen, substituted or unsubstituted    alkyl, C(O)pR13, C(O)NR13R14, SO2NR13, R14, S(O)pR15, OR15 or    NR13R14-   p is an integer from 0 to 2-   R13 and R14 are hydrogen, substituted or unsubstituted alkyl,    substituted or unsubstituted cycloalkyl, substituted or    unsubstituted heteroaryl, substituted or unsubstituted heterocycle,    substituted or unsubstituted heteroalkyl, substituted or    unsubstituted heteroaryl-heteroalkyl, or substituted or    unsubstituted aryl-heteroalkyl-   R15 is substituted or unsubstituted alkyl, substituted or    unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl,    substituted or unsubstituted heterocycle, substituted or    unsubstituted heteroalkyl, substituted or unsubstituted    heteroaryl-heteroalkyl, or substituted or unsubstituted    aryl-heteroalkyl.

SUMMARY OF THE INVENTION

The present invention relates to derivatives of formula (I) in which:

-   R3 is a (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl,    heteroaryl(1-6C)alkyl, aryl or heteroaryl fused to a (1-10C)    cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl,    polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO₂R1,    C(═NH)R1 or C(═NH)NR1 radical; these radicals optionally being    substituted by 1 or more substituents chosen from halogen, CN, NO₂,    NH₂, OH, OR1, COOH, C(O)OR1, —O—C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2,    SR1, S(O)R1, SO₂R1, NHSO₂R1, SO₂NR1R2, C(S)NR1R2, NHC(S)R1,    —O—SO₂R1, —SO₂—O—R1, aryl, heteroaryl, heterocycle, formyl,    trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or    (1-6C)alkyl;-   R5, R6 and R7 are, independently of one another, chosen from the    following radicals halogen, CN, NO2, NH₂, OH, COOH, C(O)OR8,    —O—C(O)R8, NR8R9, NHC(O)R8, C(O)NR8R9, NHC(S)R8, C(S)NR8R9, SR8,    S(O)R8, SO₂R8, NHSO₂R8, SO₂NR8R9, —O—SO₂R8, —SO₂—O—R8,    trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (1-6C)alkoxy, aryl,    aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, heterocycle,    cycloalkyl, alkenyl, alkynyl, adamantyl or polycycloalkyl; these    radicals optionally being substituted by 1 or more substituents    chosen from halogen, CN, NO₂, NH₂, OH, OR10, COOH, C(O)OR10,    —O—C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11,    SR10, S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10, —SO₂—O—R10,    aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy or    (1-6C)alkyl;-   R1, R2, R8, R9, R10 and R11 are, independently of one another, a    hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl, heteroaryl,    themselves optionally being substituted by 1 or more substituents    chosen from halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO₂, NH₂, OH,    COOH, COOalkyl, CONH₂, formyl, trifluoromethyl, trifluoromethoxy;-   R1 and R2 or R8 and R9 or R10 and R11 can form a 5- or 6-membered    ring which may or may not have a heteroatom, such as O, S or N;-   and, when R3 is a 6-membered nitrogenous heteroaryl or a thiazolyl    or an imidazolyl or an oxazolyl, then at least one of the R5 and R6    groups is an aryl which is optionally substituted by 1 or more    substituents chosen from halogen, CN, NO₂, NH₂, OH, OR10, COOH,    C(O)OR10, —O—C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10,    C(S)NR10R11, SR10, S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10,    —SO₂—O—R10, aryl, heteroaryl, formyl, trifluoromethyl,    trifluoromethoxy or (1-6C)alkyl;    to their racemates, enantiomers or diastereoisomers and their    mixtures, to their tautomers and to their pharmaceutically    acceptable salts.

More particularly, the present invention relates to derivatives offormula (I) in which:

-   R3 is a (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl,    heteroaryl(1-6C)alkyl, aryl or heteroaryl fused to a (1-10C)    cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl,    polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO₂R1,    C(═NH)R1 or C(═NH)NR1 radical; these radicals optionally being    substituted by 1 or more substituents chosen from halogen, CN, NO₂,    NH₂, OH, OR1, COOH, C(O)OR1, —O—C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2,    SR1, S(O)R1, SO₂R1, NHSO₂R1, SO₂NR1R2, C(S)NR1R2, NHC(S)R1,    —O—SO₂R1, —SO₂—O—R1, aryl, heteroaryl, heterocycle, formyl,    trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or    (1-6C)alkyl;-   R5 and R6 are chosen, independently of one another, from the    following radicals: halogen, CN, NO2, NH₂, OH, COOH, C(O)OR8,    —O—C(O)R8, NR8R9, NHC(O)R8, C(O)NR8R9, NHC(S)R8, C(S)NR8R9, SR8,    S(O)R8, SO₂R8, NHSO₂R8, SO₂NR8R9, —O—SO₂R8, —SO₂—O—R8,    trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (1-6C)alkoxy, aryl,    aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, heterocycle,    cycloalkyl, alkenyl, alkynyl, adamantyl, polycycloalkyls; these    radicals optionally being substituted by 1 or more substituents    chosen from halogen, CN, NO₂, NH₂, OH, OR10, COOH, C(O)OR10,    —O—C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11,    SR10, S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10, —SO₂—O—R10,    aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy or    (1-6C)alkyl;-   R7 is a halogen, methyl, cyclopropyl, CN, OH, methoxy,    trifluoromethyl, ethylenyl, acetylenyl, trifluoromethoxy, NO₂, NH₂    or NMe2-   R1, R2, R8, R9, R10 and R11 are, independently of one another, a    hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl or heteroaryl,    themselves optionally being substituted by 1 or more substituents    chosen from halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO₂, NH₂, OH,    COOH, COOalkyl, CONH₂, formyl, trifluoromethyl or trifluoromethoxy;-   R1 and R2 or R8 and R9 or R10 and R11 can form a 5- or 6-membered    ring which may or may not have a heteroatom, such as O, S or N;-   and when R3 is a 6-membered nitrogenous heteroaryl or a thiazolyl,    an imidazolyl or an oxazolyl, then at least one of the radicals R5    and R6 is an aryl optionally substituted by 1 or more substituents    chosen from halogen, CN, NO₂, NH₂, OH, OR10, COOH, C(O)OR10,    —O—C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11,    SR10, S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10, —SO₂—O—R10,    aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy, and    (1-6C)alkyl;    to their racemates, enantiomers or diastereoisomers and their    mixtures, to their tautomers and to their pharmaceutically    acceptable salts.

DETAILED DESCRIPTION

The present invention preferably relates to derivatives of formula (I)in which:

-   R3 is a (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl,    heteroaryl(1-6C)alkyl, aryl or heteroaryl fused to a (1-10C)    cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl,    polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO₂R1 or    C(═NH)NR1 radical; these radicals optionally being substituted by 1    or more substituents chosen from halogen, CN, NO₂, NH₂, OH, OR1,    COOH, C(O)OR1, —O—C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1,    SO₂R1, NHSO₂R1, SO₂NR1R2, C(S)NR1R2, NHC(S)R1, —O—SO₂R1, —SO₂—O—R1,    aryl, heteroaryl, formyl, oxo, trifluoromethyl,    trifluoromethylsulfanyl, trifluoromethoxy or (1-6C)alkyl;-   R5 is an aryl;-   R6 and R7 are, independently of one another, a halogen, methyl,    cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethylenyl,    acetylenyl, trifluoromethoxy, NO₂, NH₂ or NMe₂-   R1 and R2 are, independently of one another, a hydrogen,    (1-6C)alkyl, aryl, alkenyl, alkynyl or heteroaryl, themselves    optionally being substituted by 1 or more substituents chosen from    halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO₂, NH₂, OH, COOH,    COOalkyl, CONH₂, formyl, oxo, trifluoromethyl or trifluoromethoxy;-   R1 and R2 can form a 5- or 6-membered ring which may or may not have    a heteroatom, such as O, S or N;    to their racemates, enantiomers, diastereoisomers and their    mixtures, to their tautomers and to their pharmaceutically    acceptable salts.

The present invention preferably relates to derivatives of formula (I)in which:

-   R3 is a (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl,    heteroaryl(1-6C)alkyl, aryl or heteroaryl fused to a (1-10C)    cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl,    polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO₂R1 or    C(═NH)NR1 radical; these radicals optionally being substituted by 1    or more substituents chosen from halogen, CN, NO₂, NH₂, OH, OR1,    COOH, C(O)OR1, —O—C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1,    SO₂R1, NHSO₂R1, SO₂NR1R2, C(S)NR1R2, NHC(S)R1, —O—SO₂R1, —SO₂—O—R1,    aryl, heteroaryl, formyl, oxo, trifluoromethyl,    triifluoromethylsulfanyl, trifluoromethoxy or (1-6C)alkyl;-   R5 is an aryl;-   R6 is a halogen, methyl, cyclopropyl, CN, OH, methoxy,    trifluoromethyl, ethylenyl, acetylenyl, trifluoromethoxy, NO₂, NH₂    or NMe₂;-   R7 is a halogen-   R1 and R2 are, independently of one another, a hydrogen,    (1-6C)alkyl, aryl, alkenyl, alkynyl or heteroaryl, themselves    optionally being substituted by 1 or more substituents chosen from    halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO₂, NH₂, OH, COOH,    COOalkyl, CONH₂, formyl, oxo, trifluoromethyl or trifluoromethoxy;-   R1 and R2 may form a 5- or 6-membered ring optionally containing a    heteroatom such as O, S or N;    to their racemates, enantiomers or diastereoisomers and their    mixtures, to their tautomers, and to their pharmaceutically    acceptable salts.

In the preceding definitions and those which follow, the (1-6C)alkylradicals comprise 1 to 6 carbon atoms in a straight- or branched-chain;the alkenyl radicals comprise 2 to 6 carbon atoms and one to 3conjugated or nonconjugated double bonds in a straight- orbranched-chain; the alkynyl radicals comprise 2 to 6 carbon atoms andone to 3 conjugated or nonconjugated triple bonds in a straight- orbranched-chain; the aryl radicals are chosen from phenyl, naphthyl orindenyl; the heteroaryl radicals comprise 3 to 10 ring members,optionally comprising one or more heteroatoms chosen from oxygen, sulfurand nitrogen, in particular, thiazolyl, thienyl, pyrrolyl, pyridinyl,furyl, imidazolyl, oxazolyl, pyrazinyl, tetrazolyl, oxadiazolyl,thiadiazolyl, isoxadiazolyl, isothiadiazolyl, isothiazolyl, isoxazolyl,triazolyl, pyrazolyl or indolyl; the halogen radical is either chlorine,iodine, fluorine or bromine; the polycycloalkyl radicals are chosen fromadamantyl, quinuclidinyl, bornanyl, norbornanyl, bornenyl ornorbornenyl; the heteroaryl radicals fused to a (1-10C) cycloalkyl arechosen from indanyl, isochromanyl, chromanyl,1,2,3,4-tetrahydroisoquinolyl or 1,2,3,4-tetrahydroquinolyl; theheterocycle radicals comprise 1 to 2 heteroatoms chosen from oxygen,sulfur or nitrogen and represent in particular piperidinyl, morpholinyl,pyrrolidinyl, imidazolidinyl, pyrazolidinyl. isothiazolidinyl,thiazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, azetidinyl,2-piperidone, 3-piperidone, 4-piperidone, 2-pyrrolidone or3-pyrrolidone.

The compounds of formula (I) exhibiting one or more asymmetric carbonsand can therefore exist in the form of isomers, of racemates, ofenantiomers and of diastereoisomers; the latter also form part of theinvention, as do their mixtures.

Mention may be made, among the compounds of formula (I) of use accordingto the invention, of the following compounds:

-   N-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)-6-chloro-7-fluoro-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(3,3-dimethylbutyl)-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(3-phenylpropyl)-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(cyclopropylmethyl)-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(cyclopentylmethyl)-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[3-(methylthio)propyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(phenylethyl)-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(cyclohexylmethyl)-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-propyl-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(2,2,3,3,4,4,4-heptafluorobutyl)-5-phenyl-1H-indazol-3-amine    hydrate-   6-chloro-7-fluoro-N-(4,4,4-trifluorobutyl)-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[(4-methoxyphenyl)methyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(phenylmethyl)-5-phenyl-1H-indazol -3-amine-   6-chloro-7-fluoro-N-[(4-cyanophenyl)methyl]-5-phenyl-1H-indazol-3-amine-   N-[(4-chlorophenyl)methyl]-6-chloro-7-fluoro-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[(3-methoxyphenyl)methyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[[4-(trifluoromethoxy)phenyl]methyl]-5-phenyl-1H-indazol-3-amine-   N-[4-[[[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]amino]methyl]phenyl]acetamide-   6-chloro-7-fluoro-N-[(3,5-dichlorophenyl)methyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-[[4-(trifluoromethyl)phenyl]methyl]-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[(4-fluorophenyl)methyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[3-(4-methylphenoxy)phenylmethyl]-5-phenyl-1H-indazol-3-amine-   N-(2,2,3,3,4,4,4-heptafluorobutyl)-6-chloro-7-fluoro-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-[[3-(trifluoromethyl)phenyl]methyl]-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[(6-methoxy-2-naphthyl)methyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[(pentafluorophenyl)methyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[[4-(methylthio)phenyl]methyl]-5-phenyl-1H-indazol-3-amine-   N-[(4-chloro-3-fluorophenyl)methyl]-6-chloro-7-fluoro-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-(3,3,3-trifluoropropyl)-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-(3-thienylmethyl)-1H-indazol -3-amine-   N-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)-6-chloro-7-fluoro-5-phenyl-1H-indazol-3-amine-   N-(1,1′-biphenyl-4-ylmethyl)-6-chloro-7-fluoro-5-phenyl-1H-indazol    -3-amine-   6-chloro-7-fluoro-N-[[4-(dimethylamino)phenyl]methyl]-5-phenyl-1H-indazol-3-amine-   N-(2,2′-bithiophen-5-ylmethyl)-6-chloro-7-fluoro-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-[[1-(phenylmethyl)-1H-imidazol-2-yl]methyl]-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[[1-methyl-1H-imidazol-2-yl]methyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[(1-methyl-1H-indol-3-yl)methyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[(5-methyl-2-furanyl)methyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-(1H-pyrrol-2-ylmethyl)-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-[(1H-imidazol-2-yl)methyl]-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-[(1H-imidazol-4-yl)methyl]-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-(1H-pyrazol-3-ylmethyl)-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[[2-methyl-1H-imidazol-4-yl]methyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-[[2-phenyl-1H-imidazol-4-yl]methyl]-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[[5-(4-chlorophenyl)-2-furanyl]methyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-[(1-methyl-1H-pyrrol-2-yl)methyl]-1H-indazol-3-amine-   4-[5-[[[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]amino]methyl]-2-furanyl]-benzenesulfonamide-   6-chloro-7-fluoro-5-phenyl-N-(3-thienylmethyl)-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-[[2-phenyl-1H-imidazol-4-yl]methyl]-1H-indazol-3-amine-   ethyl 2-[[[6-chloro-7-fluoro-5-phenyl-1H-indazol    -3-yl]amino]methyl]-5-(methylthio)-1H-imidazole-4-carboxylate-   6-chloro-7-fluoro-5-phenyl-N-[[5-[4-(trifluoromethyl)phenyl]-2-furanyl]methyl]-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-[2-(1-piperidinyl)ethyl]-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[2-(4-morpholinyl)ethyl]-5-phenyl-1H-indazol-3-amine-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-N′-(3,5-dichlorophenyl)urea-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-N′-(2-propenyl)urea-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-N′-(phenylmethyl)urea-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-N′-(4-phenoxyphenyl)urea-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-N′-(4-methoxyphenyl)methyl]urea-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-N′-[4-(trifluoromethyl)phenyl]urea-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-N′-(4-methoxyphenyl)urea-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-N′-cyclohexylurea-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-N′-propylurea-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-N′-(4-chlorophenyl)urea-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-N′-(4-fluorophenyl)urea-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]-N′-(tricyclo[3.3.1.1^(3,7)]dec)-1-ylurea-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-N′-(4-methylphenyl)urea-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)urea-   N-(6-chloro-7-methyl-5-phenyl-1H-indazol-3-yl)urea-   N-(6-chloro-7-cyano-5-phenyl-1H-indazol-3-yl)urea-   N-(6-chloro-7-cyclopropyl-5-phenyl-1H-indazol-3-yl)urea-   N-(6-chloro-7-hydroxy-5-phenyl-1H-indazol-3-yl)urea-   N-(6-chloro-7-methoxy-5-phenyl-1H-indazol-3-yl)urea-   N-(6-chloro-7-trifluoromethyl-5-phenyl-1H-indazol-3-yl)urea-   N-(6-chloro-7-trifluoromethoxy-5-phenyl-1H-indazol-3-yl)urea-   N-(6-chloro-7-nitro-5-phenyl-1H-indazol-3-yl)urea-   N-(6-chloro-7-amino-5-phenyl-1H-indazol-3-yl)urea-   N-(6-chloro-7-dimethylamino-5-phenyl-1H-indazol-3-yl)urea-   N-(6-chloro-7-ethynyl-5-phenyl-1H-indazol-3-yl)urea-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3′-yl]-4-methyl-benzenesulfonamide-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]methanesulfonamide-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]-2-propanesulfonamide-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]-2,2,2-trifluoroethanesulfonamide-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]-2-thiophenesulfonamide-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]benzenesulfonamide-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]-4-(trifluoromethyl)benzenesulfonamide-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]-5-(3-isoxazolyl)-2-thiophenesulfonamide-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]-4-fluorobenzenesulfonamide-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]-4-methoxybenzenesulfonamide-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]benzenemethanesulfonamide-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]-1-methyl-1H-imidazole-4-sulfonamide-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]-4-(1,1-dimethylethyl)benzenesulfonamide-   N-[4-[[(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)amino]sulfonyl]phenyl]-acetamide-   N-[6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl]-4-methylbenzenemethanesulfonamide-   6-chloro-7-fluoro-N-(pentafluorophenyl)-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(3,4-difluorophenyl)-5-phenyl-1H-imidazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-(2,3,5,6-tetrafluorophenyl)-1H-indazol-3-amine-   6-chloro-7-fluoro-5-phenyl-N-(2,4,6-trifluorophenyl)-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(4-fluorophenyl)-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[3-(trifluoromethyl)phenyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[4-(trifluoromethyl)phenyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-[3-fluoro-5-(trifluoromethyl)phenyl]-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(4-nitrophenyl)-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(3-nitrophenyl)-5-phenyl- H-indazol-3-amine-   6-chloro-7-fluoro-N-(3-methoxyphenyl)-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(4-methoxyphenyl)-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N,5-diphenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(1-pyridinyl)-5-phenyl-1H-indazol-3-amine-   6-chloro-7-fluoro-N-(2-pyridinyl)-5-phenyl-1H-indazol-3-amine-   N-butyl-6-chloro-7-fluoro-5-phenyl-1H-indazol-3-amine-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-N′-phenylurea-   N-(6-chloro-7-fluoro-5-phenyl-1H-indazol-3-yl)-3-methoxybenzenesulfonamide    their isomers, their mixtures, their racemates, enantiomers,    diastereoisomers or tautomers, and their pharmaceutically acceptable    salts, and more particularly the following compound:-   Piperidine-1-carboxylic acid    (6,7-difluoro-5-phenyl-1H-indazol-3-yl)amide-   Pyrrolidine-1-carboxylic acid (6,7-difluoro-5-phenyl    -1H-indazol-3-yl)amide-   1-(6,7-Difluoro-5-phenyl-1H-indazol-3-yl)-3-[3-(4-methylpiperazin-1-yl)propyl]urea-   N-(6,7-Difluoro-5-phenyl-1H-indazol-3-yl)-N′-phenylurea    its tautomers, and their pharmaceutically acceptable salts,

The invention also relates to the pharmaceutical compositionscomprising, as active principle, a derivative of formula (I) in which

-   R3 is a (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl,    heteroaryl(1-6C)alkyl, aryl or heteroaryl fused to a (1-10C)    cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl,    polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO₂R1,    C(═NH)R1 or C(═NH)NR1 radical; these radicals optionally being    substituted by 1 or more substituents chosen from CN, NO₂, NH₂, OH,    OR1, COOH, C(O)OR1, —O—C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1,    S(O)R1, SO₂R1, NHSO₂R1, SO₂NR1R2, C(S)NR1R2, NHC(S)R1, —O—SO₂R1,    —SO₂—O—R1, aryl, heteroaryl, heterocycle, formyl, trifluoromethyl,    trifluoromethylsulfanyl, trifluoromethoxy or (1-6C)alkyl;-   R5, R6 and R7 are, independently of one another, chosen from the    following radicals halogen, CN, NO2, NH₂, OH, COOH, C(O)OR8,    —O—C(O)R8, NR8R9, NHC(O)R8, C(O)NR8R9, NHC(S)R8, C(S)NR8R9, SR8,    S(O)R8, SO₂R8, NHSO₂R8, SO₂NR8R9, —O—SO₂R8, —SO₂—O—R8,    trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (1-6C)alkoxy, aryl,    aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, heterocycle,    cycloalkyl, alkenyl, alkynyl, adamantyl or polycycloalkyl; these    radicals optionally being substituted by 1 or more substituents    chosen from halogen, CN, NO₂, NH₂, OH, OR10, COOH, C(O)OR10,    —O—C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11,    SR10, S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10, —SO₂—O—R10,    aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy or    (1-6C)alkyl;-   R1, R2, R8, R9, R10 and R11 are, independently of one another, a    hydrogen, (1-6C)alkyl,aryl, alkenyl, alkynyl, heteroaryl, themselves    optionally being substituted by 1 or more substituents chosen from    halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO₂, NH₂, OH, COOH,    COOalkyl, CONH₂, formyl, trifluoromethyl, trifluoromethoxy;-   R1 and R2 or R8 and R9 or R10 and R11 can form a 5- or 6-membered    ring which may or may not have a heteroatom, such as O, S or N;-   and, when R3 is a 6-membered nitrogenous heteroaryl or a thiazolyl    or an imidazolyl or an oxazolyl, then at least one of the R5 and R6    groups is an aryl which is optionally substituted by 1 or more    substituents chosen from halogen, CN, NO₂, NH₂, OH, OR10, COOH,    C(O)OR10, —O—C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10,    C(S)NR10R11, SR10, S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10,    —SO₂—O—R10, aryl, heteroaryl, formyl, trifluoromethyl,    trifluoromethoxy or (1-6C)alkyl;    to their racemates, enantiomers or diastereoisomers and their    mixtures, to their tautomers and to their pharmaceutically    acceptable salts.

The present invention relates more particularly to the pharmaceuticalcompositions comprising, as active principle, a derivative of formula(I) in which:

-   R3 is a (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl,    heteroaryl(1-6C)alkyl, aryl or heteroaryl fused to a (1-10C)    cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl,    polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO₂R1,    C(═NH)R1 or C(═NH)NR1 radical; these radicals optionally being    substituted by 1 or more substituents chosen from halogen, CN, NO₂,    NH₂, OH, OR1, COOH, C(O)OR1, —O—C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2,    SR1, S(O)R1, SO₂R1, NHSO₂R1, SO₂NR1R2, C(S)NR1R2, NHC(S)R1,    —O—SO₂R1, —SO₂—O—R1, aryl, heteroaryl, heterocycle, formyl,    trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or    (1-6C)alkyl;-   R5 and R6 are chosen, independently of one another, from the    following radicals: halogen, CN, NO2, NH₂, OH, COOH, C(O)OR8,    —O—C(O)R8, NR8R9, NHC(O)R8, C(O)NR8R9, NHC(S)R8, C(S)NR8R9, SR8,    S(O)R8, SO₂R8, NHSO₂R8, SO₂NR8R9, —O—SO₂R8, —SO₂—O—R8,    trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (1-6C)alkoxy, aryl,    aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, heterocycle,    cycloalkyl, alkenyl, alkynyl, adamantyl, polycycloalkyls; these    radicals optionally being substituted by 1 or more substituents    chosen from halogen, CN, NO₂, NH₂, OH, OR10, COOH, C(O)OR10,    —O—C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11,    SR10, S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10, —SO₂—O—R10,    aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy or    (1-6C)alkyl;-   R7 is a halogen, methyl, cyclopropyl, CN, OH, methoxy,    trifluoromethyl, ethylenyl, acetylenyl, trifluoromethoxy, NO₂, NH₂    or NMe2-   R1, R2, R8, R9, R10 and R11 are, independently of one another, a    hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl or heteroaryl,    themselves optionally being substituted by 1 or more substituents    chosen from halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO₂, NH₂, OH,    COOH, COOalkyl, CONH₂, formyl, trifluoromethyl or trifluoromethoxy;-   R1 and R2 or R8 and R9 or R10 and R11 can form a 5- or 6-membered    ring which may or may not have a heteroatom, such as O, S or N;-   and when R3 is a 6-membered nitrogenous heteroaryl or a thiazolyl,    imidazolyl or oxazolyl, then at least one of the radicals R5 and R6    is an aryl optionally substituted by 1 or more substituents chosen    from halogen, CN, NO₂, NH₂, OH, OR10, COOH, C(O)OR10, —O—C(O)R10,    NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11, SR10,    S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10, —SO₂—O—R10, aryl,    heteroaryl, formyl, trifluoromethyl, trifluoromethoxy and    (1-6C)alkyl;    to their racemates, enantiomers or diastereoisomers and their    mixtures, to their tautomers and to their pharmaceutically    acceptable salts.

The present invention preferably relates to the pharmaceuticalcompositions comprising, as active principle, a derivative of formula(I) in which:

-   R3 is a (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl,    heteroaryl(1-6C)alkyl, aryl or heteroaryl fused to a (1-10C)    cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl,    polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO₂R1 or    C(═NH)NR1 radical; these radicals optionally being substituted by 1    or more substituents chosen from halogen, CN, NO₂, NH₂, OH, OR1,    COOH, C(O)OR1, —O—C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1,    SO₂R1, NHSO₂R1, SO₂NR1R2, C(S)NR1R2, NHC(S)R1, —O—SO₂R1, —SO₂—O—R1,    aryl, heteroaryl, formyl, oxo, trifluoromethyl,    trifluoromethylsulfanyl, trifluoromethoxy or (1-6C)alkyl;-   R5 is an aryl;-   R6 and R7 are, independently of one another, a halogen, methyl,    cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethylenyl,    acetylenyl, trifluoromethoxy, NO₂, NH₂, NMe₂-   R1 and R2 are, independently of one another, a hydrogen,    (1-6C)alkyl, aryl, alkenyl, alkynyl or heteroaryl, themselves    optionally being substituted by 1 or more substituents chosen from    halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO₂, NH₂, OH, COOH,    COOalkyl, CONH₂, formyl, trifluoromethyl or trifluoromethoxy;-   R1 and R2 may form a 5- or 6-membered ring optionally containing a    heteroatom such as O, S or N;    to their racemates, enantiomers or diastereoisomers and to their    mixtures, their tautomers, and to their pharmaceutically acceptable    salts.

The present invention also relates to the use, as medicament, of theaminoindazole derivatives of the formula (I) in which:

-   R3 is a (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl,    heteroaryl(1-6C)alkyl, aryl or heteroaryl fused to a (1-10C)    cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl,    polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO₂R1,    C(═NH)R1 or C(═NH)NR1 radical; these radicals optionally being    substituted by 1 or more substituents chosen from CN, NO₂, NH₂, OH,    OR1, COOH, C(O)OR1, —O—C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1,    S(O)R1, SO₂R1, NHSO₂R1, SO₂NR1R2, C(S)NR1R2, NHC(S)R1, —O—SO₂R1,    —SO₂—O—R1, aryl, heteroaryl, heterocycle, formyl, trifluoromethyl,    trifluoromethylsulfanyl, trifluoromethoxy or (1-6C)alkyl;-   R5, R6 and R7 are, independently of one another, chosen from the    following radicals halogen, CN, NO2, NH₂, OH, COOH, C(O)OR8,    —O—C(O)R8, NR8R9, NHC(O)R8, C(O)NR8R9, NHC(S)R8, C(S)NR8R9, SR8,    S(O)R8, SO₂R8, NHSO₂R8, SO₂NR8R9, —O—SO₂R8, —SO₂—O—R8,    trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (1-6C)alkoxy, aryl,    aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, heterocycle,    cycloalkyl, alkenyl, alkynyl, adamantyl or polycycloalkyl; these    radicals optionally being substituted by 1 or more substituents    chosen from halogen, CN, NO₂, NH₂, OH, OR10, COOH, C(O)OR10,    —O—C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11,    SR10, S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10, —SO₂—O—R10,    aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy or    (1-6C)alkyl;-   R1, R2, R8, R9, R10 and R11 are, independently of one another, a    hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl, heteroaryl,    themselves optionally being substituted by 1 or more substituents    chosen from halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO₂, NH₂, OH,    COOH, COOalkyl, CONH₂, formyl, trifluoromethyl, trifluoromethoxy;-   R1 and R2 or R8 and R9 or R10 and R11 can form a 5- or 6-membered    ring which may or may not have a heteroatom, such as O, S or N;-   and, when R3 is a 6-membered nitrogenous heteroaryl or a thiazolyl    or an imidazolyl or an oxazolyl, then at least one of the R5 and R6    groups is an aryl which is optionally substituted by 1 or more    substituents chosen from halogen, CN, NO₂, NH₂, OH, OR10, COOH,    C(O)OR10, —O—C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10,    C(S)NR10R11, SR10, S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11,    —O—SO₂R10-SO₂—O—R10, aryl, heteroaryl, formyl, trifluoromethyl,    trifluoromethoxy or (1-6C)alkyl;    to their racemates, enantiomers or diastereoisomers and their    mixtures, to their tautomers and to their pharmaceutically    acceptable salts.

The present invention relates more particularly to the use, asmedicament, of the aminoindazole derivatives of formula (I) in which:

-   R3 is a (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl,    heteroaryl(1-6C)alkyl, aryl or heteroaryl fused to a (1-10C)    cycloalkyl, heterocycle, heterocycloalkyl, cycloalkyl, adamantyl,    polycycloalkyl, alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO₂R1,    C(═NH)R1 or C(═NH)NR1 radical; these radicals optionally being    substituted by 1 or more substituents chosen from halogen, CN, NO₂,    NH₂, OH, OR1, COOH, C(O)OR1, —O—C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2,    SR1, S(O)R1, SO₂R1, NHSO₂R1, SO₂NR1R2, C(S)NR1R2, NHC(S)R1,    —O—SO₂R1, —SO₂—O—R1, aryl, heteroaryl, heterocycle, formyl,    trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or    (1-6C)alkyl;-   R5 and R6 are chosen, independently of one another, from the    following radicals: halogen, CN, NO2, NH₂, OH, COOH, C(O)OR8,    —O—C(O)R8, NR8R9, NHC(O)R8, C(O)NR8R9, NHC(S)R8, C(S)NR8R9, SR8,    S(O)R8, SO₂R8, NHSO₂R8, SO₂NR8R9, —O—SO₂R8, —SO₂—O—R8,    trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (1-6C)alkoxy, aryl,    aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, heterocycle,    cycloalkyl, alkenyl, alkynyl, adamantyl, polycycloalkyls; these    radicals optionally being substituted by 1 or more substituents    chosen from halogen, CN, NO₂, NH₂, OH, OR10, COOH, C(O)OR10,    —O—C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11,    SR10, S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10, —SO₂—O—R10,    aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxy or    (1-6C)alkyl;-   R7 is a halogen, methyl, cyclopropyl, CN, OH, methoxy,    trifluoromethyl, ethylenyl, acetylenyl, trifluoromethoxy, NO₂, NH₂    or NMe2-   R1, R2, R8, R9, R10 and R11 are, independently of one another, a    hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl or heteroaryl,    themselves optionally being substituted by 1 or more substituents    chosen from halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO₂, NH₂, OH,    COOH, COOalkyl, CONH₂, formyl, trifluoromethyl or trifluoromethoxy;-   R1 and R2 or R8 and R9 or R10 and R11 can form a 5- or 6-membered    ring which may or may not have a heteroatom, such as O, S or N;-   and, when R3 is a 6-membered nitrogenous heteroaryl or a thiazolyl    or an imidazolyl or an oxazolyl, then at least one of the R5 and R6    groups is an aryl which is optionally substituted by 1 or more    substituents chosen from halogen, CN, NO₂, NH₂, OH, OR10, COOH,    C(O)OR10, —O—C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10,    C(S)NR10R11, SR10, S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10,    —SO₂—O—R10, aryl, heteroaryl, formyl, trifluoromethyl,    trifluoromethoxy or (1-6C)alkyl;    to their racemates, enantiomers or diastereoisomers and their    mixtures, to their tautomers and to their pharmaceutically    acceptable salts.

The present invention preferably relates to the use, as medicament, ofthe aminoindazole derivatives of formula (I) in which:

R3 is a (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl,heteroaryl(1-6C)alkyl, aryl or heteroaryl fused to a (1-10C) cycloalkyl,heterocycle, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl,alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO₂R1 or C(═NH)NR1 radical;these radicals optionally being substituted by 1 or more substituentschosen from halogen, CN, NO₂, NH₂, OH, OR1, COOH, C(O)OR1, —O—C(O)R1,NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO₂R1, NHSO₂R1, SO₂NR1R2,C(S)NR1R2, NHC(S)R1, —O—SO₂R1, —SO₂—O—R1, aryl, heteroaryl, formyl, oxo,trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or(1-6C)alkyl;

-   R5 is an aryl;-   R6 and R7 are, independently of one another, a halogen, methyl,    cyclopropyl, CN, OH, methoxy, trifluoromethyl, ethylenyl,    acetylenyl, trifluoromethoxy, NO₂, NH₂ or NMe₂-   R1 and R2 are, independently of one another, a hydrogen,    (1-6C)alkyl, aryl, alkenyl, alkynyl or heteroaryl, themselves    optionally being substituted by 1 or more substituents chosen from    halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO₂, NH₂, OH, COOH,    COOalkyl, CONH₂, formyl, oxo, trifluoromethyl or trifluoromethoxy;-   R1 and R2 may form a 5- or 6-membered ring optionally containing a    heteroatom such as O, S or N;    to their racemates, enantiomers or diastereoisomers and to their    mixtures, their tautomers, and to their pharmaceutically acceptable    salts.

The derivatives of formula (I) can be obtained from the corresponding3-amino derivatives (V) for which the nitrogen in the 1-position isoptionally protected with a group Pr. Pr is atrimethylsilylethoxymethyl, tosyl, mesyl or benzyl radical or the groupsknown for the protection of the NH groups of aromatic heterocycles asindicated in T. W. Greene, Protective Groups in Organic Synthesis, J.Wiley-Interscience Publication (1999)

The 3-amino 1H-indazoles of formula (II) can be obtained by reaction ofa 2-fluorobenzonitrile with hydrazine hydrate or hydrochloride at refluxfor 2 to 18 hours in an alcohol of ethanol or n-butanol type accordingto R. F. Kaltenbach, Bioorg. Med. Chem. Lett., 9(15), 2259-62 (1999):

The compounds for which R5 and R6 are, independently of one another,chosen from the following radicals: halogen, CN, NO₂, NH₂, OH, COOH,C(O)OR8, —O—C(O)R8, NR8R9, NHC(O)R8, C(O)NR8R9, NHC(S)R8, C(S)NR8R9,SR8, S(O)R8, SO₂R8, NHSO₂R8, SO₂NR8R9, —O—SO₂R8, —SO₂—O—R8,trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (1-6C)alkoxy, aryl,aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, cycloalkyl, alkenyl,alkynyl or adamantyl; these radicals optionally being substituted by 1or more substituents chosen from halogen, CN, NO₂, NH₂, OH, OR10, COOH,C(O)OR10, —O—C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10,C(S)NR10R11, SR10, S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10,—SO₂—O—R10, aryl, heteroaryl, formyl, oxo, trifluoromethyl,trifluoromethoxy or (1-6C)alkyl; can be obtained by reactions involvingthe chemistry of palladium: Suzuki (A. Suzuki, Pure Appl. Chem., 63,419-22 (1991), Stille (J. Stille, Angew. Chem., Int. Ed., 25, 508-24(1986)), Heck (R. F. Heck, Org. React., 27, 345-90 (1982)), Sonogashira,(K. Sonogashira, Synthesis, 777 (1977)), Buckwald (S. L. Buckwald, Acc.Chem. Re., 31, 805 (1998)), from the corresponding halogenatedderivatives.

For this, it is necessary to protect the reactive functional groups.Thus, the OH, SH, COOH and NH₂ functional groups must be protectedbefore carrying out the coupling. The protective groups are introducedaccording to any method known to a person skilled in the art and inparticular those described by T. W. Greene, Protective groups in OrganicSynthesis, J. Wiley-Interscience Publication (1999). It is preferable toprotect the nitrogen in the 1-position with groups such astert-butoxycarbonyl or silicon derivatives. The choice will preferablybe made of a tert-butyldimethylsilyl or triisopropylsilyl silyl groupwhich can be removed by fluoride anions or with acetic acid and moreparticularly a trimethylsilylethoxymethyl group which can be cleaved bytetrabutylammonium fluoride at reflux in solvents such astetrahydrofuran or dioxane (J. P. Whitten, J. Org. Chem., 51, 1891(1986); B. H. Lipshutz, Tetrahedron Lett., 4095 (1986)) or by 2Nhydrochloric acid in methanol or ethanol at reflux.

The derivatives protected in the 1-position withtrimethylsilylethoxymethyl are obtained by reacting the startingcompound with trimethylsilylethoxymethyl chloride in the presence ofsodium hydride in a solvent, such as dimethylformamide, at ambienttemperature (J. P. Whitten, J. Org. Chem., 51, 1891 (1986); M. P.Edwards, Tetrahedron, 42, 3723 (1986)).

Likewise, the 1-NH nitrogen functional group of the indazole will beprotected by groups such as silyl derivatives, benzyl, carbamate ortosyl. For example, in the case where it would be desired to carry outcoupling with palladium to a derivative halogenated in the 6-position,it will be necessary to protect the nitrogen in the 1-position as shownbelow (X═Cl, Br or I):

Deprotection is carried out according to methods known to a personskilled in the art and described by T. W. Greene, Protective Groups inOrganic Synthesis, J. Wiley-Interscience Publication (1999). Forexample, if the protective group in the 1-position is atrimethylsilylethoxymethyl, it can be deprotected by reaction withtetrabutylammonium fluoride as shown below:

When one of the R5 or R6 groups involved in the coupling using thechemistry of palladium itself comprises a reactive functional group,such as hydroxyl, amine, thiol or acid or generally includes aheteroatom, it is also necessary to protect the latter before carryingout the coupling with palladium. Thus, for example, a phenol functionalgroup will be introduced in the protected form (O-benzyl, for example)from the chlorinated derivative, the nitrogen in the 1-position beingprotected as explained previously:

The benzyl group will subsequently be removed, for example by treatmentwith trimethylsilyl iodide at reflux in acetonitrile. Protection canalso be carried out by a trimethylsilylethoxymethyl group which can becleaved by tetrabutylammonium fluoride at reflux in solvents such astetrahydrofuran or dioxane. (J. P. Whitten, J. Org. Chem., 51, 1891(1986); B. H. Lipshutz, Tetrahedron Lett., 4095 (1986)) or by 2Nhydrochloric acid in methanol or ethanol at reflux.

When R5 and R6 are, independently of one another, an aryl and a halogen,the aryl functional group is introduced from coupling with palladium toa brominated position, the nitrogen in the 1- and 3-positions beingappropriately protected. Preferably, Pr represents atrimethylsilylethoxymethyl and Pr′ represents an n-butylcarbonyl groupwhich forms, with the nitrogen, an n-butylamide. The stage ofdeprotecting the amide is carried out in the presence of ethanolamine atreflux for one week in DMF. This cleavage can also be carried out withstannous chloride in ethanol (R J Griffin, J. Chem. Soc. Perkin I, 1992,1811-1819) or else sodium methoxide in methanol (Y. Furukawa, Chem.Pharm. Bull., 1968,16, 1076) or any other alkoxide in the correspondingalcohol.

When R5 and R6 are, independently of one another, an aryl and a halogen,the aryl functional group is introduced from coupling with palladium toa brominated position, the nitrogen in the 1- and 3-positions beingappropriately protected. Preferably, Pr represents atrimethylsilylethoxymethyl and Pr′ represents an n-butylcarboxy groupwhich forms, with the nitrogen, an n-butylamide. The electrophilicsubstitution is carried out, for example, with nitroniumtetrafluoroborate (NO₂BF₄). The coupling of the 5-position is performedusing palladium chemistry (Suzuki, Heck or Sonogashira coupling). The7-position is functionalized, as a function of the desired substituents,by reductions, halogenations to introduce a bromine, or coupling bypalladium chemistry (Suzuki, Heck or Sonogashira coupling) to introducearyl, heteroaryl, alkyl, alkenyl, alkynyl or acetylenic functions. Thestage of deprotecting the amide is carried out in the presence ofethanolamine at reflux for one week in DMF. This cleavage can also becarried out with stannous chloride in ethanol (R J Griffin, J. Chem.Soc. Perkin I, 1992, 1811-1819) or else sodium methoxide in methanol (Y.Furukawa, Chem. Pharm. Bull., 1968, 16, 1076) or any other alkoxide inthe corresponding alcohol. The deprotection in the 3-position producesthe NH₂ functional group, which can react with the necessary groups tointroduce the desired substitutions into the 3-position as described inthe following pages.

The compounds of formula (II) are the starting point for the preparationof a great variety of products obtained by reaction of the primary aminefunctional group of the 3-aminoindazole in all the conventionalreactions of this functional group, such as: alkylation, acylation,reactions with carbonyl derivatives followed by reduction, sulfonation,conversion to ureas or carbamates, arylation (Castro reaction orBuchwald reaction), and the like.

The reductive aminations of derivatives of general formula (I) where R3is H when Pr is trimethylsilylethoxymethyl can be carried out usingboron derivatives, such as sodium triacetoxyborohydride, indichloromethane in the presence of an aldehyde of type R1CHO under theconditions described in Organic Reactions, Vol. 59, 1-714 (E. Baxter, A.Reitz), or by the other reducing agents commonly used to reduce imines,to form products where R3 is (1-6C)alkyl, aryl(1-6C)alkyl,heteroaryl(1-6C)alkyl, heterocycloalkyl, cycloalkyl or polycycloalkyl,these radicals optionally being substituted by 1 or more substituentschosen from halogen, CN, NO₂, NH₂, OH, OR1. COOH, C(O)OR1, —O—C(O)R1,NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO₂R1, NHSO₂R1, SO₂NR1R2,C(S)NR1R2, NHC(S)R1, —O—SO₂R1, —SO₂—O—R1, aryl, heteroaryl, formyl, oxo,trifluoromethyl, trifluoromethylsulfanyl, trifluoromethoxy or(1-6C)alkyl.

Condensations of derivatives of general formula (I) where R3 is H withisocyanates of type OCNR1 can be carried out in particular intetrahydrofuran and according to the examples described in ComprehensiveOrganic Functional Group Transformations, Vol. 6 (Katritzky, Meth-Cohn,Rees 1995), to form products where R3 is CONR1R2 or CSNR1R2, R1 and R2are, independently of one another, a hydrogen, (1-6C)alkyl, aryl,alkenyl, alkynyl or heteroaryl, themselves optionally being substitutedby 1 or more substituents chosen from halogen, (1-6C)alkyl,(1-6C)alkoxy, CN, NO₂, NH₂, OH, COOH, COOalkyl, CONH₂, formyl, oxo,trifluoromethyl or trifluoromethoxy.

Sulfonations of derivatives of general formula (I) where R3 is H can becarried out from a sulfonyl chloride of R1SO₂Cl type in the presence ofa base (in particular tertiary amines, such as triethylamine, oraromatic amines, such as pyridine) in a conventional solvent, such as,for example, dichloromethane, to form the products where R3 is SO₂R1 andR1 is a hydrogen, (1-6C)alkyl, aryl, alkenyl, alkynyl or heteroaryl,themselves optionally being substituted by 1 or more substituents chosenfrom halogen, (1-6C)alkyl, (1-6C)alkoxy, CN, NO₂, NH₂, OH, COOH,COOalkyl, CONH₂, formyl, oxo, trifluoromethyl or trifluoromethoxy.

The compounds of formula (I) are isolated and can be purified by theusual known methods, for example by crystallization, chromatography orextraction.

The compounds of formula (I) can optionally be converted to additionsalts with an inorganic or organic acid by the action of such an acid inan organic solvent, such as an alcohol, ketone, an ether or achlorinated solvent. These salts also form part of the invention.

Mention may be made, as examples of pharmaceutically acceptable salts,of the following salts: benzenesulfonate, hydrobromide, hydrochloride,citrate, ethanesulfonate, fumarate, gluconate, iodate, maleate,isethionate, methanesulfonate, methylenebis-β-oxynaphthoate, nitrate,oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate,theophyllineacetate and p-toluenesulfonate.

The compounds of formula (I) are kinase inhibitors and are thus of usein the prevention and treatment of neurodegenerative diseases,Alzheimer's disease, Parkinson's disease, frontoparietal dementia,corticobasal degeneration, Pick's disease, strokes, cranial and spinaltraumas and peripheral neuropathies, obesity, essential hypertension,atherosclerotic cardiovascular diseases, polycystic ovaries syndrome,syndrome X, immunodeficiency and cancer.

The activities were determined by measuring the inhibition of thephosphorylation of the tau protein in adult rat cortex sections.

Cortex sections with a thickness of 300 μm are prepared from male OFArats (Iffa-Credo) aged 8-10 weeks, sacrificed by decapitation. They areincubated in 5 ml of DMEM medium comprising pyruvate and glucose 4.5 g/lat 37° C. for 40 min. The sections are subsequently washed twice withthe medium, distributed in microtubes (50 μl in 500 μl of medium, withor without test compounds) and incubated at 37° C. with stirring. Twohours later, the experiment is halted by centrifuging. The sections arelyzed, sonicated and centrifuged at 18300 g for 15 min at 4° C. Theconcentration of proteins in the supernatant is determined by acommercial assay (BCA Protein Assay, Pierce) based on the Lowry method.

The samples, denatured beforehand at 70° C. for 10 min, are separated on4-12% Bis-tris vertical gel in the presence of MOPS-SDS buffer and areelectrotransferred onto a nitrocellulose membrane. Immunolabeling iscarried out with the monoclonal antibody AD2, which specificallyrecognizes the Ser396/404 phosphorylated epitopes of the tau protein.The immunoreactive proteins are visualized by addition of a secondantibody directed against mouse IgGs and coupled to peroxidase and of achemoluminescent substrate. The autoradiograms obtained are finallyquantified using the ‘GeneTools’ software from Syngene (GeneGnome,Ozyme) to determine an IC₅₀ value.

The compounds of formula (I) exhibit a highly advantageous activity andin particular some compounds have an IC₅₀ value of less than 100

M.

The following examples illustrate the invention without impliedlimitation.

The conditions for analysis of the products by LC/MS were produced on aWaters Alliance 2695 device for the LC part and a Waters-MicromassPlatform II for the mass part.

Preparation of the Intermediate Products:

6,7-Difluoro-1H-imidazole-3-amine

0.32 cm³ of hydrazine monohydrate is added to 0.46 cm³ of2,3,4-trifluorobenzonitrile in 10 cm³ of absolute ethanol. The medium isheated at about 75° C. for 17 hours, followed by addition of 10 cm³ ofethyl acetate, 5 cm³ of tetrahydrofuran and 5 cm³ of distilled water.The organic phase is separated out after settling the phases and iswashed with 10 cm³ of distilled water and then with 10 cm³ of saturatedaqueous sodium chloride solution. The organic phase is separated outafter settling the phases, dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (2 kPa; 50° C.). Theresidue obtained is purified by chromatography under an argon pressureof 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter1.5 cm), eluting with a cyclohexane/ethyl acetate mixture (50/50 byvolume). The fractions containing the expected product are combined andthen evaporated under reduced pressure (2 kPa; 40° C.); after drying (90Pa; 40° C.), 100 mg of 6,7-difluoro-1H-indazole-3-amine are obtained inthe form of a white solid melting at 183° C.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6,

in ppm): 5.57 (unresolved complex: 2H); 6.93 (mt: 1H); 7.52 (ddd,J=8.5-4.5 and 1 Hz: 1H); 12.01 (unresolved complex: 1H).

N-(6,7-Difluoro-1H-indazol-3-yl)butanamide

0.61 cm³ of butyryl chloride is added to 1 g of6,7-difluoro-1H-indazole-3-amine described above, in 15 cm³ of pyridine,after having cooled to about 3° C., and the mixture is then left atambient temperature for 76 hours. The reaction medium is concentratedunder reduced pressure (2 kPa; 40° C.) and the residue is taken up in 25cm³ of ethyl acetate and 25 cm³ of water. The organic phase is washedwith 25 cm³ of distilled water and then with 25 cm³ of saturated aqueoussodium chloride solution. After drying over magnesium sulfate, filteringand concentrating under reduced pressure (2 kPa; 40° C.), the residueobtained is purified by chromatography under an argon pressure of 50kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm),eluting with a dichloromethane/methanol mixture (98/2 by volume). Thefractions containing the expected product are combined and thenevaporated under reduced pressure (2 kPa; 40° C.); after drying (90 Pa ;40° C.), 596 mg of N-(6,7-difluoro-1H-indazol-3-yl)butanamide areobtained in the form of a white solid melting at 191° C.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6,

in ppm): 0.97 (t, J=7.5 Hz: 3H); 1.67 (mt: 2H); 2.40 (t, J=7 Hz: 2H);7.10 (mt: 1H); 7.63 (broad dd, J=9 and 4.5 Hz 1H); 10.47 (broadunresolved complex: 1H); 13.35 (broad unresolved complex: 1H).

N-[6,7-Difluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide

A solution of 1.1 g of N-(6,7-difluoro-1H-indazol-3-yl)butanamideprepared above, in 180 cm³ of dimetlhylformamide, is added dropwise over3 hours to 1.65 g of sodium hydride at 60% in oil, in 50 cm³ ofdimethylformamide. The reaction medium is concentrated to dryness underreduced pressure and taken up in 250 cm³ of ethyl acetate and 200 cm³ ofwater; the organic phase is separated out after settling of the phases,washed with 150 cm³ of water, dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (2 kPa; 50° C.). Thecrude product is purified by chromatography under an argon pressure of50 kPa, on a column of silica gel (particle size 40-60 μm ; diameter 6cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume).The fractions containing the expected product are combined andevaporated under reduced pressure (2 kPa; 50° C.) to give 7.3 g ofN-[6,7-difluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamidein the form of a yellow oil.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6,

in ppm): -0.09 (s: 9H); 0.82 (t, J=8 Hz: 2H); 0.96 (t, J=7.5 Hz: 3H);1.67 (mt: 2H); 2.41 (t, J=7 Hz: 2H); 3.56 (t, J=8 Hz: 2H); 5.66 (s: 2H);7.22 (ddd, J=11-9 and 7 Hz: 1H); 7.69 (broad dd, J=9 and 4.5 Hz: 1H);10.60 (unresolved complex: 1H).

Mass spectrum: M=369

N-[5-Bromo-6,7-difluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]-butanamide

0.87 cm³ of pyridine is added to 1 g ofN-[6,7-difluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamidedescribed above in 30 cm³ of chloroform, followed by addition of 0.56cm³ of bromine, and the mixture is refluxed overnight. 50 cm³ ofdichloromethane and 50 cm³ of aqueous 10% sodium thiosulfate solutionare added to the reaction medium. After stirring for 10 minutes, theinsoluble material is removed by filtration on a sinter funnel and theorganic phase is washed with 50 cm³ of water and with 50 cm³ ofsaturated sodium chloride solution. The organic phase is separated outby settling of the phases, dried over magnesium sulfate, filtered andconcentrated to dryness under reduced pressure (2 kPa; 45° C.). Thecrude product, 1.1 g, is purified by chromatography under an argonpressure of 50 kPa, on a column of silica gel (particle size 40-60 μm ;diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10by volume). The fractions containing the expected product are combinedand evaporated under reduced pressure (2 kPa; 50° C.). After drying (90Pa; 45° C.), 230 mg ofN-[5-bromo-6,7-difluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamideare obtained in the form of a colorless oil.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6,

in ppm): −0.08 (s: 9H); 0.82 (t, J=8 Hz: 2H); 0.96 (t, J=7.5 Hz: 3H);1.67 (mt: 2H); 2.42 (t, J=7 Hz: 2H); 3.55 (t, J=8 Hz: 2H); 5.66 (s: 2H);8.08 (dd, J=6 and 2 Hz: 1H); 10.72 (unresolved complex: 1H).

Mass spectrum: M=447

N-[6,7-Difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]-butanamide

469 mg of phenylboronic acid, 760 mg of sodium carbonate in 30 cm³ ofwater and 379 mg of tetrakis(triphenylphosphine)palladium are added to1.15 g ofN-[5-bromo-6,7-difluoro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamideprepared above, in 150 cm³ of dioxane, and the mixture is refluxed for 4hours. The reaction medium is diluted with 100 cm³ of ethyl acetate and75 cm³ of water and is filtered through a sinter funnel packed withCelite. The organic phase is separated out after settling of the phases,washed with 75 cm³ of water and with 75 cm³ of saturated sodium chloridesolution, dried over magnesium sulfate, filtered and concentrated todryness under reduced pressure (2 kPa; 50° C.) to give 2 g of crudeproduct in the form of a black oil. The crude product is purified bychromatography under an argon pressure of 50 kPa, on a column of silicagel (particle size 40-60 μm ; diameter 3.5 cm), eluting with acyclohexane/ethyl acetate mixture (85/15 by volume). The fractionscontaining the expected product are combined, evaporated under reducedpressure (2 kPa; 50° C.) and dried (90 Pa, 45° C.) to give 1.1 g ofN-[6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamidein the form of a yellow oil.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6,

in ppm): −0.05 (s: 9H); 0.84 (t, J=8 Hz: 2H); 0.95 (t, J=7.5 Hz: 3H);1.66 (mt: 2H); 2.43 (t, J=7 Hz: 2H); 3.59 (t, J=8 Hz: 2H); 5.69 (s: 2H);from 7.40 to 7.65 (mt: 5H); 7.82 (broad d, J=7 Hz: 1H); 10.64(unresolved complex: 1H).

Mass spectrum: M=445

N-[6,7-Difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazole-3-amine

1.1 cm³ of ethanolamine and then 1.50 g of potassium carbonate are addedto 1.6 g ofN-[6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]-butanamidedescribed above, in 50 cm³ of dimethylformamide, and the mixture isrefluxed for one week. The reaction medium is concentrated to drynessunder reduced pressure and taken up in 150 cm³ of ethyl acetate and 75cm³ of water. The organic phase is separated out after settling of thephases and washed successively with twice 75 cm³ of water and 50 cm³ ofbrine. The organic phase is dried over magnesium sulfate, filtered andthen concentrated to dryness under reduced pressure (2 kPa; 50° C.). Thecrude oil obtained is purified by chromatography under an argon pressureof 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume).The fractions containing the expected product are combined andevaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa;45° C.), 0.32 g of6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazole-3-amineis obtained.

6,7-Difluoro-5-phenyl-1H-indazole-3-amine

1.1 ml of 2N HCl are added to 661 mg of6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazole-3-aminein 15 ml of methanol. The reaction is subjected to microwaves for 3minutes at 140° C. After hydrolysis with saturated KH₂PO₄ solution andextraction with methylene chloride, the solvents are evaporated off andthe residue is chromatographed on silica (methylene chloride/ethylacetate) to give 314 mg of 6,7-difluoro-5-phenyl-1H-indazole-3-amine.

EXAMPLE 1 Piperidine-1-carboxylic acid(6,7-difluoro-5-phenyl-1H-indazol-3-yl)amide

Step 1

131 μl of pyridine and 154 μl of ethyl chloroformate are successivelyadded to 387.8 mg of(6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazole-3-aminecompound in 8 ml of methylene chloride. After 75 minutes, the reactionis complete. After hydrolysis, extraction and evaporation, 840 mg ofcrude ethyl (6,7-difluoro-5-phenyl-1H-indazol-3-yl)carbamate areobtained.

Step 2

184 mg of piperidine are added to 161 mg of crude ethyl(6,7-difluoro-5-phenyl-1H-indazol-3-yl)carbamate in 2.5 ml oftrifluorotoluene and the reaction is performed under microwaves for 20minutes at 200° C. After purification by preparative LC/MS(acetonitrile/pH 9 buffer), 80 mg of piperidine-1-carboxylic acid(6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl)amideare obtained.

Step 3

80 mg of piperidine-1-carboxylic acid(6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl)amidein 2.5 ml of methanol are treated with 0.82 ml of 2N HCl for 1 hour atreflux. After evaporation and purification by preparative LC/MS(acetonitrile/pH 9 buffer), 11 mg of piperidine-1-carboxylic acid(6,7-difluoro-5-phenyl-1H-indazol-3-yl)amide are obtained.

Mass spectrum: retention time 3.99; 357=[M+H]⁺

¹H NMR spectrum (300 MHz, (DMSO-d6,

in ppm): 1.50 (m, 4H); 1.58 (m, 2H); 3.45 (m, 4H); 7.42 (m, 1H); 7.51(m, 5H); 9.16 (s, 1H); 13.20 (bs, 1H)

EXAMPLE 2 Pyrrolidine-1-carboxylic acid(6,7-difluoro-5-phenyl-1H-indazol-3-yl)amide

Step 1

154 mg of pyrrolidine are added to 161 mg of ethyl(6,7-difluoro-5-phenyl-1H-indazol-3-yl)carbamate in 2.5 ml oftrifluorotoluene, and the reaction is performed under microwaves for 20minutes at 200° C. The product is purified on a column of silica to give75 mg of pyrrolidine-1-carboxylic acid(6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl)amide.

Step 2

75 mg of pyrrolidine-1-carboxylic acid(6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl)amidein 3 ml of methanol are treated with 0.82 ml of 2N HCl for 1 hour atreflux. After evaporation and purification by preparative LC/MS(acetonitrile/pH 9 buffer), 36 mg of pyrrolidine-1-carboxylic acid(6,7-difluoro-5-phenyl-1H-indazol-3-yl)amide are obtained.

Mass spectrum: retention time 3.72 minutes; 343=[M+H]⁺

¹H NMR spectrum (300 MHz, (DMSO-d6,

in ppm): 1.86 (m, 4H); 3.40 (m, 4H) 7.42 (m, 1H); from 7.45 to 7.54 (m,4H); 7.63 (bd, J=7 Hz, 1H); 8.84 (s, 1H); 13.20 (bs, 1H)

EXAMPLE 3 Performed According to Example 2, Starting with3-(4-methylpiperazin-1-yl)propylamine, to give1-(6,7-difluoro-5-phenyl-1H-indazol-3-yl)-3-[3-(4-methylpiperazin-1-yl)propyl]urea

¹H NMR spectrum (300 MHz, (DMSO-d6,

in ppm): 1.92 (m, 2H); 2.82 (s, 3H); from 3.01 to 3.75 (m, partiallymasked, 12H); 7.43 (m, 1H); from 7.47 to 7.56 (m, 4H); 7.71 (t, J=7 Hz,1H); 8.05 (dd, J=1.5-7 Hz, 1H); 9.61 (s,1H)

Mass spectrum: retention time 2.57 minutes; 429=[M+H]⁺

The pharmaceutical compositions according to the invention are composedof a compound of formula (I) or a salt of such a compound, in the purestate or in the form of a composition in which it is combined with anyother pharmaceutically compatible product, which can be inert orphysiologically active. The medicaments according to the invention canbe employed orally, parenterally, rectally or topically.

Use may be made, as solid compositions for oral administration, tablets,pills, powders (of hard gelatin capsules, cachets) or granules. In thesecompositions, the active principle according to the invention is mixedwith one or more inert diluents, such as starch, cellulose, sucrose,lactose or silica, under an argon stream. These compositions can alsocomprise substances other than the diluents, for example one or morelubricants, such as magnesium stearate or talc, a colorant, a coating(dragees) or a glaze.

Use may be made, as liquid compositions for oral administration, ofpharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs comprising inert diluents, such as water, ethanol, glycerol,vegetable oils or liquid paraffin. These compositions can comprisesubstances other than the diluents, for example wetting, sweetening,thickening, flavoring or stabilizing products.

The sterile compositions for parenteral administration can preferably besolutions in aqueous or nonaqueous form, suspensions or emulsions. Usemay be made, as solvent or vehicle, of water, propylene glycol, apolyethylene glycol, vegetable oils, in particular olive oil, injectableorganic esters, for example ethyl oleate, or other suitable organicsolvents. These compositions can also comprise adjuvants. in particularwetting, isotonizing, emulsifying, dispersing and stabilizing agents.Sterilization can be carried out in several ways, for example by asepticfiltration, by incorporating sterilizing agents in the composition, byirradiation or by heating. They can also be prepared in the form ofsterile solid compositions which can be dissolved at the time of use insterile water or any other injectable sterile medium.

The compositions for rectal administration are suppositories or rectalcapsules which comprise, in addition to the active product, excipientssuch as cocoa butter, semisynthetic glycerides or polyethylene glycols.

The compositions for topical administration can be, for example, creams,lotions, eye drops, mouthwashes, nose drops or aerosols.

The subject matter of the invention is the aminoindazole compounds offormula (I) and their pharmaceutically acceptable salts and their use inthe preparation of pharmaceutical compositions intended to prevent andtreat diseases which result from an abnormal activity of kinases, suchas, for example, those involved in neurodegenerative diseases,Alzheimer's disease, Parkinson's disease, frontoparietal dementia,corticobasal degeneration, Pick's disease, strokes, cranial and spinaltraumas and peripheral neuropathies, obesity, metabolic diseases, typeII diabetes, essential hypertension, atherosclerotic cardiovasculardiseases, polycystic ovaries syndrome, syndrome X, immunodeficiency andcancer.

Mention may be made, as abnormal kinase activity, of, for example, thatof PI3K, AkT or GSK3beta, of CDKs, and the like.

In human therapy, the compounds according to the invention are ofparticular use in the treatment and/or prevention of neurodegenerativediseases, Alzheimer's disease, Parkinson's disease, frontoparietaldementia, corticobasal degeneration, Pick's disease, strokes, cranialand spinal traumas and peripheral neuropathies, obesity, metabolicdiseases, type II diabetes, essential hypertension, atheroscleroticcardiovascular diseases, polycystic ovaries syndrome, syndrome X,immunodeficiency and cancer.

The doses depend on the desired effect, on the duration of the treatmentand on the administration route used; they are generally between 5 mgand 1000 mg per day orally for an adult with unit doses ranging from 1mg to 250 mg of active substance.

Generally, the doctor will determine the appropriate dosage according tothe age, weight and all the other factors specific to the subject to betreated.

The following examples illustrate compositions according to theinvention:

EXAMPLE A

Hard gelatin capsules, with doses of 50 mg of active product, having thefollowing composition are prepared according to the usual technique:

Compound of formula (I) 50 mg Cellulose 18 mg Lactose 55 mg Colloidalsilica  1 mg Sodium carboxymethylstarch 10 mg Talc 10 mg Magnesiumstearate  1 mg

EXAMPLE B

Tablets, with doses of 50 mg of active product, having the followingcomposition are prepared according to the usual technique:

Compound of formula (I) 50 mg Lactose 104 mg  Cellulose 40 mg Polyvidone10 mg Sodium carboxymethylstarch 22 mg Talc 10 mg Magnesium stearate  2mg Colloidal silica  2 mg Mixture of hydroxymethylcellulose, glyceroland titanium 245 mg  oxide (72/3.5/24.5) q.s. for 1 coated tabletcompleted to

EXAMPLE C

An injectable solution comprising 10 mg of active product having thefollowing composition is prepared:

Compound of formula (I) 10 mg Benzoic acid 80 mg Benzyl alcohol 0.06 mlSodium benzoate 80 mg 95% Ethanol 0.4 ml Sodium hydroxide 24 mgPropylene glycol 1.6 ml Water q.s. for 4 ml

The present invention also relates to the method for the prevention andtreatment of diseases in which a phosphorylation of the tau protein isinvolved by administration of a compound of formula (I) and itspharmaceutically acceptable salts.

1. A method of treating a disease selected from the group consisting of:obesity and stroke, comprising administering to a subject in needthereof, an effective amount of a compound of formula (I):

wherein R3 is a (1-6C)alkyl, aryl, aryl(1-6C)alkyl, heteroaryl,heteroaryl(1-6C)alkyl, aryl or heteroaryl fused to a (1-10C) cycloalkyl,heterocycle, heterocycloalkyl, cycloalkyl, adamantyl, polycycloalkyl,alkenyl, alkynyl, CONR1R2, CSNR1R2, COOR1, SO₂R1, C(═NH)R1 or C(═NH)NR1radical; these radicals optionally being substituted by 1 or moresubstituents chosen from halogen, CN, NO₂, NH₂, OH, OR1, COOH, C(O)OR1,—O—C(O)R1, NR1R2, NHC(O)R1, C(O)NR1R2, SR1, S(O)R1, SO₂R1, NHSO₂R1,SO₂NR1R2, C(S)NR1R2, NHC(S)R1, —O—SO₂R1, —SO₂—O—R1, aryl, heteroaryl,heterocycle, formyl, trifluoromethyl, trifluoromethylsulfanyl,trifluoromethoxy or (1-6C)alkyl; R5, R6 and R7 are, independently of oneanother, chosen from the following radicals: halogen, CN, NO2, NH₂, OH,COOH, C(O)OR8, —O—C(O)R8, NR8R9, NHC(O)R8, C(O)NR8R9, NHC(S)R8,C(S)NR8R9, SR8, S(O)R8, SO₂R8, NHSO₂R8, SO₂NR8R9, —O—SO₂R8, —SO₂—O—R8,trifluoromethyl, trifluoromethoxy, (1-6C)alkyl, (1-6C)alkoxy, aryl,aryl(1-6C)alkyl, heteroaryl, heteroaryl(1-6C)alkyl, heterocycle,cycloalkyl, alkenyl, alkynyl, adamantyl or polycycloalkyl; theseradicals optionally being substituted by 1 or more substituents chosenfrom halogen, CN, NO₂, NH₂, OH, OR10, COOH, C(O)OR10, —O—C(O)R10,NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10, C(S)NR10R11, SR10, S(O)R10,SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10, —SO₂—O—R10, aryl, heteroaryl,formyl, trifluoromethyl, trifluoromethoxy or (1-6C)alkyl; R1, R2, R8,R9, R10 and R11 are, independently of one another, a hydrogen,(1-6C)alkyl, aryl, alkenyl, alkynyl, heteroaryl, themselves optionallybeing substituted by 1 or more substituents chosen from halogen,(1-6C)alkyl, (1-6C)alkoxy, CN, NO₂, NH₂, OH, COOH, COOalkyl, CONH₂,formyl, trifluoromethyl, trifluoromethoxy; R1 and R2 or R8 and R9 or R10and R11 can form a 5- or 6-membered ring which may or may not have aheteroatom, such as O, S or N; and, when R3 is a 6-membered nitrogenousheteroaryl or a thiazolyl or an imidazolyl or an oxazolyl, then at leastone of the R5 and R6 groups is an aryl which is optionally substitutedby 1 or more substituents selected from halogen, CN, NO₂, NH₂, OH, OR10,COOH, C(O)OR10, —O—C(O)R10, NR10R11, NHC(O)R10, C(O)NR10R11, NHC(S)R10,C(S)NR10R11, SR10, S(O)R10, SO₂R10, NHSO₂R10, SO₂NR10R11, —O—SO₂R10,—SO₂—O—R10, aryl, heteroaryl, formyl, trifluoromethyl, trifluoromethoxyand (1-6C)alkyl; or a racemate, an enantiomer or a diastereoisomer or amixture thereof, or a tautomer or a pharmaceutically acceptable saltthereof.
 2. The method according to claim 1, wherein the disease isobesity.
 3. The method according to claim 1, wherein the disease isstroke.